Particles are important class of materials in medicine and other applications. Particles exist at nanometer or micrometer sizes and are used in a wide range of applications, including pharmaceuticals, medical devices, research tools, cosmetics, paints and inks, industrial applications, as well as others. For example, a major challenge for many active pharmaceutical ingredients (therapeutic materials) is the inability to deliver adequate concentrations to target cells to elicit a biological affect. Certain therapeutic materials, including many chemotherapeutic materials, are toxic and cannot be administered systemically at doses that are required to have an affect on a disease, while others, including many biologics like oligonucleotide therapeutic materials, are unable to cross cell membranes to access their site of action. Polymers, lipids and other materials offer a promising solution for encapsulating therapeutic materials and transporting them to diseased cells and tissues in particles. Such particles can increase a therapeutic material's therapeutic index by reducing toxicity through shielding the therapeutic material from healthy tissues, increasing the therapeutic material effectiveness through targeting diseased tissue, and by enabling the active delivery of therapeutic materials to their site of action.
A variety of methods have been developed to manufacture particles. These methods include self-assembly, precipitation, and homogenization. Various devices, including microfluidic devices have demonstrated the ability to controllably and rapidly mix fluids in continuous flow formats with precise control over temperature, residence times, and solute concentrations. Microfluidics has proven applications for the synthesis of inorganic nanoparticles and microparticles, and can outperform macroscale systems in large-scale production of particles. Droplet techniques have been applied to produce monodisperse microparticles for therapeutic material delivery or to produce large vesicles for the encapsulation of cells, proteins, or other biomolecules. Hydrodynamic flow focusing, a common microfluidic technique to provide rapid mixing of reagents, has been used to create monodisperse lipid particles of controlled size. This technique has also proven useful in the production of polymer particles where smaller, more monodisperse particles were obtained, with higher encapsulation of small molecules as compared to bulk production methods. Turbulent mixers, including T, W, or Y mixers with channel dimensions >0.1 mm have been successfully used for the manufacture of microparticles and nanoparticles.
Despite the availability of methods of manufacture for particle systems, the manufacture of high quality particles at small scales (<1 mL) remains at challenge due to the difficulties of mixing very small volumes together effectively and the wastage of fluids, or fluidic “dead volume,” in the devices and in connections to the devices. The present invention seeks to fulfill this need and provides further related advantages.